Clinical manifestations

Presentation and course

The hallmarks of tetanus are sustained muscular rigidity and, in severe cases, reflex spasms. In most cases, a portal of entry can be identified; however, the lack of a defined wound does not exclude tetanus.

Clinically, tetanus can be classified into local and generalized forms (21; 12). The interval between the time of spore inoculation and development of first symptoms is referred as “incubation period,” which may vary from a few days to weeks. The time from the first symptoms to reflex spasms is known as period of onset. This temporal progression of symptoms determines the disease severity.

Early manifestations of generalized tetanus are rigidity of the masseter muscles (trismus, or lockjaw) and facial muscles, with straightening of the upper lip (grimace, or risus sardonicus).

Localized stiffness near the injury may be present. These symptoms are soon followed by rigidity of axial musculatures with predominant involvement of neck, back muscles (opisthotonos), and abdomen. Frequently, rigidity of axial parts precedes or appears simultaneously with lockjaw. As the disease progresses, stiffness of limb muscles also becomes evident with relative sparing of distal parts. Paroxysmal, violent contractions of the involved muscles (reflex spasms) appear repetitively only in severe cases in response to attempts at voluntary movement and to even slight external and internal (fear, hunger, etc.) stimuli. Trismus and spasms of deglutition muscles (in severe cases) cause difficulties in swallowing and in verbal expression. Generalized spasms, as well as laryngospasm, contribute to ventilatory insufficiency and asphyxia. The alteration of consciousness and true convulsive seizures are the consequence of severe cerebral hypoxia rather than the disease per se. The severity of symptoms continues to increase for 10 to 14 days after onset, and recovery usually begins after 4 weeks.

Autonomic instability, mostly hypersympathetic state, may complicate severe cases (75). Fluctuations of blood pressure and heart rate are cardinal features. These may be followed by arrhythmias and circulatory failure. Profuse sweating, hypersalivation, and extreme hyperpyrexia are also commonly present.

Patients who have an incubation period between 10 to 14 days and a period of onset of over 3 to 6 days with infrequent reflex spasms are classified as having a moderate degree of severity. A shorter incubation period and period of onset accompanied by respiratory compromise and frequent and violent spasms with severe dysphagia are regarded as evidence of severe generalized form.

Neonatal tetanus usually occurs as a generalized form and carries a high mortality. The disorder usually develops during the first 2 weeks in children born to inadequately immunized mothers and frequently follows umbilical stump infection. Some birth practices performed in developing countries, such as application of clarified butter (ghee) heated with contaminated dung fuel on an umbilical wound or wrapping an infant in sheepskin after dry cow dung is applied (bundling), are risk factors for neonatal tetanus (09; 08; 77). Failure to suck and twitching are the most frequent symptoms of neonatal tetanus.

Fixed muscular rigidity confined to a wound-bearing extremity is the characteristic of local tetanus and may persist for months. However, it is more common that local tetanus is a forerunner of the generalized form. Cephalic tetanus is a specialized form of local tetanus, presenting as trismus plus paralysis of one or more cranial nerves. Facial paresis and dysphagia are common presentations. Abnormal ocular movements including bilateral trochlear nerve palsy (ophthalmoplegic tetanus) and downbeat nystagmus can be present (59). Cephalic tetanus is usually associated with infections of paracranial structures, especially chronic otitis media and dental infection (12).

Prognosis and complications

Prognosis depends on the temporal progression, degree of clinical severity, presence of autonomic instability, portal of entry, and age. Burns, infected umbilical stumps, septic abortion, intramuscular injection, and compound fractures are often related to poor outcome. Tetanus that follows intramuscular quinine injection carries high mortality with a rapidly fatal course (80). Poor prognostic factors for neonatal tetanus includes age less than 10 days on admission, symptom duration less than 5 days on admission, risus sardonicus, fever, infant weight of less than 2500 g, and increase in white blood cells (33; 24; 42).

Complications include pneumonia, fractures, muscle ruptures, rhabdomyolysis, and renal failure. Tetanus-induced acute renal failure is probably related to adrenergic overactivity (22). Phrenic and laryngeal neuropathies as well as toxic axonal polyneuropathy have also been found as consequences (48).

Clinical vignette

A 32-year-old previously healthy male was brought to the emergency room because of difficulty in swallowing and chewing. He reported having punctured his right foot with a nail 7 days previously. He did not receive any antitetanus antiserum or tetanus toxoid. His immunization record showed that he had completed primary immunization program during childhood but had received no booster. Physical examination revealed trismus and rigidity involving facial and trunk muscles. The wound at the right sole was infected. He was diagnosed as having tetanus and was admitted to the hospital.

Human tetanus immune globulin was given intramuscularly. The wound was cleansed thoroughly. Amoxicillin-clavulanate (1.2 g every 8 hours intravenously) and metronidazole (500 mg every 6 hours intravenously) were given and continued for 10 days. A nasogastric tube was inserted. Diazepam was administered intravenously to control muscle rigidity.

Despite such treatments, his condition deteriorated in the following days. Rigidity spread to the limbs and torso. Spasms occurred spontaneously and in response to external stimuli. Rigidity and spasm were severe enough to compromise respiration. An endotracheal tube was inserted after administration of pancuronium. Tracheostomy was performed thereafter, and respiration was assisted by mechanical ventilator. Pancuronium was given intravenously every 2 to 3 hours and was continued for 4 weeks. Substantial improvement was evident at the end of the fourth week. Rigidity improved, requiring fewer doses of pancuronium. In the sixth week, rigidity was controlled by diazepam alone. He recovered uneventfully and was discharged after 8 weeks.

Biological basis

Etiology and pathogenesis

Tetanus is caused by the neurotoxin tetanospasmin, produced by an anaerobic motile gram-positive rod, Clostridium tetani. The mature form has a slender shape with a terminal spherical spore. Spores may survive several years and are resistant to various disinfectants and to boiling for 20 minutes. Under an appropriate anaerobic condition, contaminated spores start to germinate and proliferate to easily inactivated vegetative cells with subsequent production of two exotoxins: tetanolysin and tetanospasmin. The clinical relevance of tetanolysin in tetanus is still uncertain. The complete genome sequence of Clostridium tetani has been reported (16).

The thermolabile neurotoxin tetanospasmin, a zinc metalloprotease, which is responsible for the clinical tetanus, is a single 1315-amino acid polypeptide chain of 151 kd, formed in vegetative cells under plasmid control. The native nonvirulent or low-virulent molecule becomes toxic after being cleaved at serine-458 by a bacterial protease resulting in a heterodimer of one heavy (100-kd) and one light (50-kd) chain connected by a disulfide bridge (10). This bridge as well as a second bridge on the heavy chain is required for the toxin activity (40). By using papain that cleaves the heavy chain at lysine-865, this toxin molecule can be divided into three fragments. C fragment is a 50-kd carboxy-terminal polypeptide. The remaining A-B fragment is the light chain and the amino-terminal end of the heavy chain, joined by a disulfide bridge. The C fragment is responsible for attachment and internalization of toxin, whilst the A-B fragment involves the inhibition of neurotransmitter release. Tetanus toxin entry into vertebrate motoneurons may involve binding of neuronal surface gangliosides containing the “1b” substructure (70). This toxin internalizes the lumen of synaptic vesicles via the process of vesicular reuptake. Vesicle acidification is essential for the toxin translocation in the cytosol where it exerts its neurotoxic effect (50).

Any breach in skin or mucosal barrier may result in the inoculation of C tetani spores. Wounds that provide an anaerobic condition (low oxidation-reduction potential), eg, those associated with a severe degree of tissue necrosis, foreign bodies, or active infection with other organisms, are more prone to produce tetanus. Toxin released in the wound binds to the peripheral nerve terminals directly, as in the case of local tetanus, or may disseminate via the bloodstream to neuromuscular junctions throughout the body before binding in generalized form (61). The toxin gains access to the CNS by retrograde axonal transport along the motor nerves. Within the CNS, the toxin moves transsynaptically into presynaptic inhibitory interneurons where inhibition of the release of neurotransmitters (mainly GABA in brainstem and glycine in spinal cord) takes place, resulting in heightened muscular activity (53). By a similar process, loss of glycine inhibition may affect preganglionic sympathetic neurons in the intermediolateral gray matter of the spinal cord and produce increased sympathetic activity with markedly increased catecholamine levels. This inhibitory action is mediated by protease activity of light chain on synaptobrevin at Gln 76 to Phe 77 (43; 69). Synaptobrevin (also known as vesicle-associated membrane protein or VAMP) is an integral membrane protein of small synaptic vesicles and is essential for docking vesicles into release site on synaptic membrane. Motor neurons can also be similarly affected causing the reduction in the release of acetylcholine at the motor end plate. This may account for the paralysis of cranial nerves observed in cephalic tetanus. However, in general, this prejunctional effect on the neuromuscular junction is usually overwhelmed by the central disinhibition of motor neurons.

Epidemiology

Tetanus occurs worldwide but is more prevalent in developing countries. About 1 million cases (18 per 100,000) are estimated to occur annually (30). During 2001 to 2016, an average incidence rate of 0.09 per million person-years was reported in the United States (71). The case-fatality rate was 13.2% among 197 patients with known outcome. Incidence was higher among persons aged 65 years or older, persons with diabetes, and injection drug users. The rate among Hispanics was nearly twice that among non-Hispanics (19). In developing countries of Africa, a systematic review and meta-analysis shows a crude case-fatality rate to be 43.2% despite of its decline in incidence. The major issue was due to low quality of medical care and lack of mechanical ventilators (79).

Neonatal tetanus is the second leading cause of death from vaccine preventable diseases among children worldwide. In 2013, neonatal tetanus was estimated to be responsible for 49,000 deaths and accounts for 1% of total child death (44). However, the incidence was small in the United States.

Prevention

Wounds with severe tissue necrosis, suppuration, and retained foreign bodies (eg, burns, umbilical stumps, compound fractures, septic abortion, intramuscular injection) are associated with high risk of tetanus. Appropriate wound care and immunization are the main preventive strategies.

In preventing tetanus, certain immunizations are available in forms of both active (tetanus toxoid) and passive (tetanus specific immunoglobulin) immunizations. Active immunizations come in forms of toxoid that can rather be administered alone as single toxoid (TT) or in combination with diphtheria (DT, dT) or diphtheria with acellular pertussis (DTwP, DTaP, dTaP or dTaP). In some countries, combining tetanus with hepatitis B, Haemophilus influenzae type b, and poliomyelitis may be used. It is advised that combination vaccines should be selected first rather than tetanus toxoid alone. DT vaccines are recommended to be use in children younger than 7 years of age whereas dT vaccines for those 7 and older are recommended. A WHO expert consultation panel concluded that dT could be used in children aged 4 to 7 years as a second booster dose in the 6-dose series and that this regimen could provide adequate protection to tetanus and diphtheria (27). Passive immunizations come in forms of tetanus immunoglobulin (TIG) used to neutralize tetanospasmin and circulating toxins.

The DTP combination (primarily for children aged less than 1 year) has been part of The World Health Organization’s Expanded Program on Immunization since its inception in 1974. The primary set of DTP consists of three doses (DTP3) that should be given to infants in their first 6 months of life with at least 4-week intervals for each dose. This primary series is the fundamental requirement in building a lifelong immunity. WHO suggests that in maintaining a lifelong immunity, three additional doses are required at the age of 12 to 23 months, 4 to 7 years, and 9 to 15 years of age with a 4-year interval to each dose (78). This practice is also recommended by the Centers for Disease Control and Prevention but with an additional recommendation of a single booster every 10 years (17; 18; 20). Prophylactic administration of antipyretic drugs at the time of vaccination to prevent febrile reaction can minimize the antibody response and, therefore, is not recommended as routine practice (62).

Preterm infants have a similar antibody response after completion of the primary series of regular vaccines (23). Reduction of vaccine dosage for preterm infants may result in inadequate immunity (11). The antibody titer to routine tetanus immunization can be reduced in preterm infants who receive dexamethasone, but the level is still above protective level. Therefore, additional booster vaccination for these infants is not necessary (64). Breastfeeding (more than 6 months) can increase immunity against tetanus (60).

Unvaccinated adults or those with incomplete history of primary prevention vaccination should undergo a primary prevention of three doses tetanus-containing vaccine; administer the first two doses at least 4 weeks apart and the third dose 6 to 12 months after the second. Further recommendation suggests that for maintaining a lifelong immunity, an additional two doses are preferred. A booster dose of tetanus-containing vaccines is given to individuals in whom childhood primary vaccination was completed and last dose was given 10 years or more previously (78).

Specific risk patients may need reimmunization; this includes recipients of bone marrow transplantation because of the loss in protective immunity (45). HIV patients have been reported to have a lower response to tetanus vaccination as its disease progresses, but they still show a positive response compared with other vaccinations (66). Antibody monitoring after tetanus immunization may be necessary in special groups of patients, such as those receiving hemodialysis, because a high percentage of recipients do not show documentable seroconversion after standard immunization (41). For previously immunized travelers to endemic areas and healthcare workers, there is no evidence that revaccination is needed. Another group of patients that might need attention are diabetic patients. Diabetic patients have a lower level of tetanus antitoxin compared to nondiabetic people. In addition, patients with diabetic foot are more prone to tetanus (38; 35).

Vaccination in pregnant women is an emerging concern in the prevention of neonatal tetanus and will be discussed in the pregnancy section.

In case of injuries, patients who have completed the primary vaccination within 5 years for tetanus-prone wounds and within 10 years for clean wounds do not require booster immunization. Patients with tetanus-prone wounds with incomplete immunization or no immunization within the preceding 10 years should receive human tetanus immunoglobulin 250 IU intramuscularly on a separate site with a different syringe from that used for the tetanus containing vaccine (78). Patients with immunodeficient states should also receive passive immunization after injuries unless adequate immunity to tetanospasmin has been demonstrated (12).

Tetanus toxoid is considered very safe, even for use in immunodeficient individuals. Adverse effects of tetanus toxoid are usually mild (local tenderness and edema). In general, both local and systemic reactions increase with increasing numbers of doses. Granuloma formations at the injection sites and Arthus reactions especially after boosters have been reported. Therefore, tetanus-diphtheria toxoid boosters should not be given to anyone who has either completed a primary series or received a booster dose within the previous 5 years. On rare occasions, nervous system complications, eg, acute radiculomyelitis parkinsonism, brachial neuritis, or Guillain-Barré syndrome, can develop following the administration of tetanus toxoid (72; 06; 34; 63). Tetanus vaccination is not associated with an elevated risk of multiple sclerosis exacerbation (46).

Differential diagnosis

Confusing conditions

Diagnostic workup

Diagnosis of tetanus is usually based on clinical findings. A history of open-wound injuries or presence of portal of entry supports the diagnosis. The reflex spasm of the masseter on touching the posterior pharyngeal wall, the so-called positive spatula test, was observed in most cases and may help in diagnosing tetanus (04).

In settings when clinical diagnosis is uncertain, laboratory investigations may play a role in diagnosis of tetanus. Culture of C tetani from infected wounds has a high diagnosis value but only one third of cases will be culture positive. Serum anti-tetanus immunoglobulin titers can also be helpful. A serum antitetanus immunoglobulin above 0.01 IU/ml suggests a protective level that helps support the unlikeliness of tetanus, but a case of fatal tetanus with protective level of serum antibody has been reported (01). Polymerase chain reaction and levels of serum tetanus toxin may be helpful but still have not been definitively studied. In addition, electrophysiology methods have also been reported to be helpful. Abnormal electromyography characterized by continuous spontaneous motor unit discharge can be observed in affected muscles (49). A transient, diffusely abnormal EEG has also been found during the acute phase of the infection (47).

Management

Elimination of the source of toxin, toxin neutralization, control of muscle rigidity and spasms, and ventilator support are the main strategies in treatment of tetanus (21; 12).

The first step of tetanus management is to consider prophylactic intubation and mechanical ventilation, particularly in moderate to severe tetanus. Intubation may still be necessary even in the absence of severe or frequent spasms, especially in patients with severe generalized rigidity within a few days after the first clinical symptoms and in patients whose incubation periods are shorter than 10 days (severity continues for 10 to 14 days after onset). The drawback of an endotracheal tube is that it stimulates spasms; as a result, tracheostomy should be considered to prevent further damage (55).

Identification of the portal of entry and wound dressing are necessary in every tetanus patient. In cases without an apparent source, careful examination for signs of parenteral drug abuse, otitis, or rectal or vaginal instrumentation should be attempted. Improper wound care with retaining of foreign body may result in continuous toxin production. Antibiotic therapy is usually recommended despite the controversy of its benefit. Metronidazole (500 mg intravenously every 6 hours for 7 to 10 days) is the drug of choice and has shown better survival, shorter hospital stays, and less disease progression compared with the alternative penicillin (02). Parenteral administration of penicillin (10 to 12 million U daily for 10 days) is an alternative. Because penicillin has central GABA antagonistic effect; however, it may act synergistically with tetanospasmin and worsen spasms. Clindamycin and erythromycin are also alternatives for penicillin-allergic patients.

Neutralization of circulating (unbound) toxin by antitoxin will shorten the course of disease and lower mortality. Human tetanus immune globulin should be administered promptly before manipulating the wound. The recommended dose is 500 U intramuscularly. Combined intrathecal (1000 U) and intramuscular antitetanus immunoglobulin administration gives better clinical outcomes than intramuscular administration alone (51). A meta-analysis based on results from 12 clinical trials confirmed the benefit of using intrathecal therapy over intramuscular administration. The combined relative risk of mortality for intrathecal versus intramuscular therapy was 0.71 (95%CI, 0.62-0.81) (36). In addition to clinical outcome, intrathecal immunoglobulin also reduces cost by preventing a worsening of disease severity and shortening hospital stay (52). Equine antitetanus serum (doses up to 10,000 to 100,000 U) is an alternative in case human tetanus immune globulin is not available, but it should be used after testing and desensitization. A primary immunization series is also required in addition to human tetanus immune globulin.

For control of muscle spasms and rigidity, several drugs have been proven to be beneficial. Benzodiazepines are key medications for controlling spasms because of their action as GABA agonists. Diazepam is the most preferable drug of its kind due to its widely studied benefits. A dose of 5 mg is given intravenously with an incremental dose of up to 600 mg until spasm is controlled but without ventilatory depression (76). Lorazepam and midazolam have no solid evidence of efficacy compared with diazepam but can be used as alternatives (65). Phenobarbitone and chlorpromazine have also been used worldwide, but a study shows that diazepam alone is more effective than combination of phenobarbitone and chlorpromazine (57). In patients whose spasms could not be controlled with benzodiazepine or in severe cases with ventilation failure, neuromuscular junction blockade using agents such as atracurium, vecuronium, or pancuronium, are preferred. Propofol has also proven to be effective, but its side effects, including metabolic acidosis, rhabdomyolysis, and cardiac arrhythmia, should be considered (58). Intravenous magnesium sulphate alone has been reported to effectively control both muscle spasms and autonomic dysfunction in a prospective study of 40 patients (05).

Intrathecal baclofen (infusion or intermittent injections) may be effectively used as a single therapy in moderately severe cases (67; 29). However, risk of developing central depression with coma and respiratory failure after frequent injections precludes its use as a routine in tetanus treatment. Flumazenil has been used to counteract these adverse effects (68).

Autonomic instability has been a troublesome problem due to its lack of positive response to medication. Combined alpha- and beta-adrenergic blocking agents such as labetalol, have been tried with some success. Beta-adrenergic blockade is rarely used because hypotension and sudden cardiac arrest may occur. Only esmolol was proved to be effective in a case report (39). Other alternatives include parenteral administration of morphine, fentanyl, magnesium sulfate, clonidine, atropine, and continuous spinal anesthesia (12; 32). Magnesium infusion can reduce the requirement for other drugs to control muscle spasms and cardiovascular instability but does not reduce the need for mechanical ventilation in adults with severe tetanus (74). In medication-refractory autonomic instability cases, stellate ganglion blocks were reported to show control over autonomic storm, but further study is needed (03).

Special considerations

Pregnancy

Maternal tetanus is tetanus occurring during pregnancy or within 6 weeks after any type of pregnancy. Approximately 15,000 to 30,000 cases of maternal tetanus occur in developing countries each year (31). No further data have been reported thus far, but incidence of maternal tetanus is likely to have fallen due to maternal vaccine coverage (73). Neonatal tetanus is defined as any neonate with normal sucking in the first 2 days who then cannot suck normally between 3 to 28 days and has spasm and stiffness (78).

In preventing both maternal and neonatal tetanus, safe deliveries, umbilical cord care, and maternal immunization are of extreme importance. However, the most cost-effective prevention is complete vaccination. Studies suggest that a complete set of six doses of tetanus-containing vaccine in childhood or five doses at adolescence can prevent both maternal tetanus and neonatal tetanus, with no need for further immunization (26). For countries where tetanus is endemic, at least two doses of tetanus-containing vaccines are recommended. Each dose should be 4 weeks apart with the last dose at least 2 weeks before delivery. For those with only three doses in childhood, an additional two doses are recommended (78). A study showed that antepartum Tdap vaccination produces no adverse pregnancy outcomes for either mother or child (54). The mortality associated with postpartum tetanus is comparable to nonpostpartum cases, and early hysterectomy has no effect on its outcome (37).

Immunization for pregnant women is also effective in preventing cases of and deaths from neonatal tetanus. A meta-analysis showed that immunization of pregnant women or women of childbearing age with at least two doses of tetanus toxoid is estimated to reduce mortality from neonatal tetanus by 94% (95% confidence interval 80% to 98%) (13). Tetanus toxoid immunogenicity as well as maternal-fetal antibody transfer can be affected by various factors, including maternal vitamin A deficiency, maternal HIV infection, and placental infection with falciparum malaria (14; 25; 28). Freezing tetanus toxoid has been shown to decrease its potency, but its impact on immunogenicity needs more evaluation.